Data presented at SUO indicated that MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau disease-associated clear cell renal cell carcinoma, pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.
Study results presented at the 21st Annual Meeting of the Society of Urologic Oncology (SUO) indicated that MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC), pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.
In an interview with CancerNetwork®, Ramaprasad Srinivasan, MD, PhD, investigator and head of the Molecular Cancer Therapeutics Section in the Center for Cancer Research at the National Cancer Institute, discussed the study design and what led to the development of this study
So, let me give you a little bit of background to start with. VHL is, as you know, a disease associated with an increased risk of developing tumors in multiple organ systems, including the development of bilateral multifocal… so, kidney cancer. Traditionally, this disease is managed surgically, or sometimes with ablative procedures. In the context of kidney cancers, the goal of surgery is to minimize the risk of metastatic spread. So usually when tumors reach the size of around 3 centimeters or so, we think there begins to exist a risk for metastatic spread, and the bigger the tumor gets, the more the risk of metastatic spread. And so, it's to prevent this or minimize the risk of this metastatic spread that people remove these tumors, usually with a nephron sparing procedure.
New tumors keep growing because the basic issue, which is germline VHL mutation driving this process, isn't being taken away by surgical procedures, and so patients often undergo multiple surgical procedures in their lifetime. And when you add the surgical procedures occurring in the kidney, in the CNS, for pancreas, and other things, it gets to be quite burdensome for the patients over the course of their lifetime.
An attempt to treat patients with systemic therapy, you know, has been… several attempts have been made over the last several years. Initially, based on our understanding of the biology of VHL loss and how that leads to tumorigenesis… targeted agents were designed, evaluated, found to be effective in metastatic kidney cancer and the same agents were then tried in patients with VHL. We tried to see if we could trim their tumors and maybe minimize the need for surgery or delay the need for surgery. While several of these studies suggested that you could reasonably shrink tumors in the kidneys, we found that what was an acceptable toxicity profile for patients with metastatic kidney cancer wasn't necessarily so for patients with VHL.
These patients have, you know, a very, very different, you know, prognosis, very different outlook, very different lifestyles than patients with metastatic kidney cancer do and consequently, their ability to tolerate some side effects is very different from those in metastatic kidney cancer patients. So, in my experience, it's been very hard to effectively deliver VEGF targeted therapy in patients with VHL. And I've never really viewed it as a viable option for the majority of patients, particularly for long term years. In addition, it's been my experience, and those of others that you don't see much by way of responses in the central nervous system… tumors. And there's very little experience in… with regard to pancreatic tumors, particularly neuroendocrine tumors in the pancreas. So for all these reasons, it's very clear that if you had an agent that was one more effective and to better tolerated, we might begin to make an impact on these patients and maybe just begin to move away from surgery to some extent, or at least minimize the lifetime surgical burden of some of these patients. And so that was the logic really in trying to devise the study with MK6482.
Now, why MK-6482? It’s a drug that... It's one of the group of agents that was developed initially by a company that was then taken over, but the idea was to selectively inhibit HIF-2α. This is a transcription factor that we think plays an important role in mediating cancer formation in in the setting of VHL loss, which is what we see in VHL patients. So, we think HIF-2α plays a very, very critical role and the two agents develop sort of in parallel, one called PD2385, was available for clinical use first. And indeed, it was looked at in both sporadic cancer kidney cancer patients and patients with VHL associated kidney cancer. We had a very small phase two trial with that agent in VHL patients and very quickly found that although the agent had some potential, there were some issues with the pharmacokinetics – the way the drug was handled by the body – such that not all patients, you know, achieved reliable levels of the drug in their system. So, with the availability of MK6482, which was a sister drug, with much, much better pharmacokinetic properties, attention quickly shifted to this drug. And this phase two study was designed really to address the question of whether we could control, shrink, or stabilize tumors in the kidneys, as well as some other tumors that are associated with VHL with this drug. The other end points… whether or not patients tolerated this drug. And so that really was the basis for the study.
The design was very, very simple. We… treat approximately 50 patients and then we treated around 61 patients on the study and wanted to ask what proportion of patients had what we call an objective response by in a traditional research criteria when looking only at the kidney tumors. So, we looked at the kidney tumors separately and determined what the number of responders was. And we did the same for other organ systems. So, each organ system was individually reviewed, so we would be able to calculate overall response rate in the CNS, for instance, or the pancreas. And that was essentially the rationale for designing the study and a very simple overview of the study design.